a) Low Dose Estrogen Regimens
In the past years, it has been recognized that there are certain benefits associated with steroid based oral contraceptives, i.e. OCs, having lower doses of progestin, and especially, lower doses of estrogen. Such benefits of lower estrogen doses include decreased incidence of nuisance side effects, such as, nausea, vomiting, and gastric upset, as well as a decreased incidence of serious side effects, such as, thromboembolism, stroke, and myocardial infarction. Thus, while the advantages of steroid based contraceptives are well established in the medical community, it is desirable to administer the lowest effective dose of steroids, on a patient by patient basis, in order to minimize these types of side effects.
A principle problem with lower doses of estrogen in an OC regimen is poor cycle control and the patient compliance problems associated with poor cycle control. At estrogen doses below 30 .mu.g per day, it has been observed that the incidence of breakthrough bleeding and/or spotting is increased to the point that many women can be expected to experience additional discomfort due to irregular bleeding. This failure to control the cycle will lead many women to unnecessarily return to higher estrogen doses, stop using contraception or fall out of compliance with the prescribed regimen. It is well recognized that the symptoms of poor cycle control influence the occurrence of unintended pregnancies by encouraging the cessation of OC use by women who do not wish to become pregnant.
Endrikat, J.; U. Muller, and B. Dusterberg; Contraception 1997; 55: 131-137 compared a 20 .mu.g and 30 .mu.g ethinyl estradiol (EE) monophasic regimen for cycle control. In this regimen, women received either tablets containing 20 .mu.g of EE and 75 .mu.g gestodene or 30 .mu.g of EE and 75 .mu.g of gestodene. The regimen was a monophasic 21 days of active tablets followed by a tablet-free period of 7 days. A higher incidence of breakthrough bleeding and/or spotting was apparent for the 20 .mu.g EE regimen. The breakthrough bleeding and/or spotting results disclosed by this article are more fully summarized below as COMPARATIVE EXAMPLE A.
Tuimala, R.; M. Saranen; and U. Alapiessa; Acta Obstet Gynecol Scand 1994; 144: 7-12 compared a 20 .mu.g and 30 .mu.g ethinyl estradiol (EE) monophasic regimen for cycle control. In this regimen, women received either tablets containing 20 .mu.g of EE and 150 .mu.g desogestrel or 30 .mu.g of EE and 150 .mu.g desogestrel. The regimen was a monophasic 21 days of active followed by a tablet-free period of 7 days. A higher incidence of breakthrough bleeding and/or spotting was apparent for the 20 .mu.g EE regimen. The breakthrough bleeding and/or spotting results disclosed by this article are more fully summarized below as COMPARATIVE EXAMPLE B.
Akerlund, M.; A. Rode; and J. Westergaard; Brit J Obstet Gynecol September 1993; 100: 832-838 compared a 20 .mu.g and 30 .mu.g ethinyl estradiol (EE) monophasic regimen for cycle control. In this regimen, women received either tablets containing 20 .mu.g of 15 EE and 150 .mu.g desogestrel or 30 .mu.g of EE and 150 .mu.g desogestrel. The regimen was a monophasic 21 days of active followed by a tablet-free period of 7 days. A higher incidence of breakthrough bleeding and/or spotting was apparent for the 20 .mu.g EE regimen. The breakthrough bleeding and/or spotting results disclosed by this article are more fully summarized below as COMPARATIVE EXAMPLE C.
Darney, P.; and C. Klaisle; Dialogues in Contraception; Vol. 5, Number 5, Univ. of Southern California School of Medicine, survey various literature sources and conclude that OCs containing 20 .mu.g estrogen, such as a monophasic regimen containing 20 .mu.g EE and 100 .mu.g levonorgestrel, have higher rates of breakthrough bleeding and spotting than do formulations containing 30 or 35 .mu.g estrogen.
Task Force on Oral Contraceptives--WHO Special Program of Research, Development, and Research Training in Human Reproduction; Contraception 1982; Vol. 25, Number 3, demonstrates that a combination of 1 mg norethindrone acetate and 50 .mu.g of EE has better cycle control than a combination of 1 mg norethindrone acetate and 20 .mu.g of EE.
Thus, there exists a need for an OC containing an estrogen dose of less than 30 .mu.g per day yet having cycle control equivalent to an OC of higher estrogen content.
b) Triphasic Regimens
Three-stage or triphasic combination type oral contraceptive regimens are known. Triphasic regimens of various types are described in U.S. Pat. Nos. 4,390,531; 4,066,757; 3,957,982; 3,795,734; and 2,431,704.
More recently, Pasquale S., U.S. Pat. Nos. 4,530,839; 4,544,554; 4,616,006; and 4,628,051 described a triphasic regimen of contraception which comprises administering for 21 successive days to a female of childbearing age a combination of an estrogen and a progestogen in a low but contraceptively effective daily dosage corresponding in estrogenic activity to 20-50 .mu.g of 17.alpha.-ethinylestradiol and in progestogenic activity to 0.065-0.75 mg of norethindrone for 5-8 days; for the next 7-11 days an estrogen daily dosage equal to 20-50 .mu.g of 17.alpha.-ethinylestradiol and in progestogenic activity to 0.250-1.0 mg of norethindrone; and for the next 3-7 days an estrogen daily dosage equal to 20-50 .mu.g of 17.alpha.-ethinylestradiol and in progestogenic activity 0.35-2.0 mg of norethindrone; followed by 6-8 days without estrogen and progestogen administration, provided that the estrogen daily dosage is the same for each period. The purpose of this regimen is to lower the total monthly steroid dose in the oral contraceptive while still obtaining equivalent bleeding patterns and protection against pregnancy as found with conventional oral contraceptives.
Particular triphasic regimens of Pasquale have met with considerable commercial success. One commercial regimen with norgestimate has been marketed by Ortho-McNeil Pharmaceutical Inc. in the United States under the trademark ORTHO TRI-CYCLEN. According to this regimen, there is administered 7 days of a tablet containing 35 .mu.g 17.alpha.-ethinylestradiol and 0.180 mg norgestimate, followed by 7 days of a tablet containing 35 .mu.g 17.alpha.-ethinylestradiol and 0.215 mg norgestimate, followed by 7 days of a tablet containing 35 .mu.g 17.alpha.-ethinylestradiol and 0.250 mg norgestimate, followed by 7 days of a placebo. Another commercial regimen with norethindrone has been marketed by Ortho-McNeil Pharmaceutical Inc. in the United States under the trademark ORTHO-NOVUM 7/7/7. According to this regimen, there is administered 7 days of a tablet containing 35 .mu.g 17.alpha.-ethinylestradiol and 0.5 mg norethindrone, followed by 7 days of a tablet containing 35 .mu.g 17.alpha.-ethinylestradiol and 0.75 mg norethindrone, followed by 7 days of a tablet containing 35 .mu.g 17.alpha.-ethinylestradiol and 1.0 mg norethindrone, followed by 7 days of a placebo. These regimens have proven particularly successful at controlling the cycle of women as well as protecting against pregnancy at relatively low total monthly steroid doses.
There is a need, however, for a combination type contraceptive which contains even lower total monthly steroid doses, particularly of estrogen, yet is still effective for the prevention of pregnancy and maintains a high level of cycle control.
There remains a need for a triphasic regimen of contraception with substantially lower doses of estrogen, yet does not exhibit a substantial loss of cycle control.